Direct and Differential Suppression of Myeloid-Derived Suppressor Cell Subsets by Sunitinib Is Compartmentally Constrained

Abstract

The anti-angiogenic drug sunitinib is a receptor tyrosine-kinase inhibitor with significant, yet not curative, therapeutic impacts in metastatic renal cell carcinoma (mRCC). Sunitinib is also an immunomodulator, potently reversing myeloid-derived suppressor cell (MDSC) accumulation and T-cell inhibition in the blood even of non-responder RCC patients. We observed that sunitinib similarly prevented MDSC accumulation and restored normal T-cell function to spleens of tumor-bearing mice, independent of sunitinib's capacity to inhibit tumor progression (RENCA>CT26>4T1). Both monocytic and neutrophilic splenic MDSC were highly repressible by sunitinib. In contrast, MDSC within the microenvironment of 4T1 tumors or human RCC tumors proved highly resistant to sunitinib, and ambient T-cell function remained suppressed. Proteomic analyses comparing tumor to peripheral compartments demonstrated that GM-CSF predicted sunitinib resistance, and recombinant GM-CSF conferred sunitinib resistance to MDSC in vivo and in vitro. MDSC conditioning with GM-CSF uniquely inhibited STAT3 and promoted STAT5 activation, and STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. We conclude that compartment-dependent GM-CSF exposure in resistant tumors may account for sunitinib's regionalized impact upon host MDSC modulation, and hypothesize that ancillary strategies to decrease such regionalization will enhance sunitinib's potency as an immunomodulator and a cancer therapy.

TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function

“…12 As these cells are known to impair tumor immunity, different strategies have been applied to target MDSC in cancer. Several approaches are under investigation to inhibit these cells pharmacologically, including the induction of MDSC apoptosis (by gemcitabine, sunitinib, or 5-fluorouracil) [25][26][27] , the inhibition of MDSC function (with sildenafil and cyclooxygenase 2 inhibitors) 28,29 and the promotion of maturation of MDSC into nonsuppressive cells (all-trans retinoic acid, vitamin D). 30 Here, we have shown that TLR7 stimulation leads to the upregulation of maturation markers on MDSC in vitro, a finding that is in accordance with previous reports.…”

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

“…In addition, sunitinib has been demonstrated to reverse the MDSC accumulation in patients with renal cell carcinoma (RCC), resulting in the accumulation of Th1 cells and the reduction of Tregs [101]. Such beneficial sunitinib effect was also found in the murine RCC model correlated with the neutralization of immunosuppressive functions of tumor-infiltrating MDSCs [100].…”

“…One of main targets in the circumvention of MDSC formation is stem cell factor (SCF). The knockdown of SCF with siRNA and the prevention of SCF signaling by anti-c-kit antibodies or tyrosine kinase inhibitors such as sunitinib, pazopanib and sorafenib have been reported to reduce frequencies of MDSCs developed from human bone marrow precursors in vitro and in murine models of colon and Lewis lung carcinoma [99,100]. In mice, a decrease of MDSC levels was associated with enhanced tumor-specific immune responses, tumor regression and significantly prolonged survival.…”

Immunomodulatory effects of anti-angiogenic drugs

“…Sunitinib has shown the potential to modulate antitumor immunity by reversing the MDSC accumulation. [8][9][10] The reduction in MDSC correlated with a reversal of type 1 T-cell suppression, an effect that could be reproduced by the depletion of the MDSC in vitro. 8 Interestingly, MDSC reduction in response to sunitinib went in line with a reversal of Treg elevation.…”